Modulation of cytokine production by 7-hydroxycoumarin in vitro and its efficacy against influenza infection in mice

Abstract

We previously demonstrated that 7-hydroxycoumarin (7HC) was effective in reducing proinflammatory cytokine production in lipopolysaccharide-exposed macrophage-like P388D1 cells and fever production by suppressing the increase in interleukin (IL)-1α production in an influenza virus-intranasal infection model in mice. In this study, we assessed the effects of modulation of cytokine production by 7HC on influenza virus infection in relation to its efficacy in influenza virus-infected mice. 7HC was confirmed to suppress proinflammatory cytokine levels in P388D1 cells due to influenza virus infection. In the murine infection model, oral administration of 7HC (30 mg/kg) was significantly effective in reducing the weight loss of infected mice and virus titers in the bronchoalveolar lavage fluid (BALF) of lungs and in prolonging survival times without toxicity. The rise of proinflammatory and Th1 cytokine (IL-12 and interferon-γ) production in the BALF from infected mice was significantly suppressed by 7HC at two and four days post-infection, respectively. This suppression correlated with the reduction of virus titers and diminution of lung consolidation. Because 7HC did not exhibit direct anti-influenza virus activity in vitro, 7HC was suggested to suppress pneumonia in influenza virus-infected mice through suppression of the cytokine production induced by infection.